From Cell Death and Activation to Paralysis: Dysregulated Conventional Dendritic Cells in SIRS, Sepsis and Major...

Conventional dendritic cells (cDC) are pivotal for initiating antigen-specific T-cell responses. Upon encountering pathogen- and damage-associated molecular patterns (PAMPs/DAMPs) or inflammation, cDC undergo direct or indirect activation. Directly activated cDC acquire additional antigens and present them to prime T-cells but become unresponsive to new antigens. In contrast, indirectly activated cDC remain capable of efficient antigen presentation upon subsequent exposure to PAMPs/DAMPs. Due to cDC's short lifespan, activated cDC are replenished within days by newly generated immature/resting cDC. However, during systemic inflammatory response syndrome (SIRS), early depletion and systemic activation of cDC can occur, followed by prolonged reprogramming that yields functionally impaired or paralyzed/regulatory cDC. These dysfunctional cDC populations contribute to post-SIRS immunosuppression. Gradual resolution of the immunoregulatory microenvironment allows repopulation with functionally competent cDC over subsequent weeks or months, necessary for restoring immunocompetence. In this review, we summarize current understanding of the sequential alterations in cDC population during SIRS, sepsis, and major trauma. We discuss the mechanistic basis of cDC dysfunction in these conditions as well as in tumors, highlighting shared and distinct pathways of dysregulation. We further elaborate on emerging therapeutic strategies aimed at restoring cDC function to improve immune recovery and clinical outcomes in critically ill patients.